Temporal multi-omic exploration of the ventral tegmental area in chronic pain and passive coping behaviors

The comorbidity of chronic pain and mood disorders poses a clinical challenge involving neurobiological mechanisms within key brain regions like the ventral tegmental area (VTA). We employed a multidisciplinary approach in male mice, combining proteomics, phosphoproteomics, and lipidomics with behavioral and immunohistochemical analyses in a neuropathic pain model. Our findings reveal a temporal evolution of the VTA molecular landscape-an early signature related to metabolic reallocation followed by a late maladaptive state characterized by shifts in energy metabolism and cytoskeletal remodeling. This late maladaptive state involved stoichiometric remodeling of Kv7 potassium channel subunits and depletion of the endocannabinoid 2-arachidonoylglycerol (2-AG), coinciding with the passive coping behavior. Pharmacological administration of 2-AG or potentiation of Kv7 channel function reversed pain-induced passive coping. Together, these findings delineate a temporal molecular evolution in the VTA and validate 2-AG and Kv7 systems as regulatory nodes linking chronic pain to the emergence of passive coping behaviors.